CTGF-associated cancers include more common forms of cancer such as breast and colon cancer and also some of the most deadly such as pancreatic cancer and gliomas, including glioblastomas. Pancreatic cancer claims the lives of approximately 35,000 individuals in the US every year. Incidence rates are similar to mortality rates. Frequently, a diagnosis of pancreatic cancer is made at an advanced stage that precludes surgical excision of tumor masses. Treatment with the chemotherapy agent gemcitabine, used alone or in combination with other drugs, is the standard of care, but, despite therapy, patients survive only about 6 months from time of diagnosis. In the absence of treatment, the survival time is only 2 to 4 months.
The role of CTGF as the central mediator of tissue remodeling and fibrosis (persistent and excessive scarring) is well established in the scientific literature. Several recent studies also implicate CTGF in tumor progression, including tumor cell survival and metastasis. CTGF promotes epithelial to mesenchymal transition (EMT), a process whereby normal epithelial cells become migratory, matrix-producing fibroblasts that have been shown to be important during invasion and metastasis (Burns W C, et al. J Am Soc Nephrol. 2006 September; 17(9):2484-94; Yang J and Weinberg R A. Dev Cell. 2008 June; 14(6):818-29)). Elevated CTGF levels are found in desmoplastic cancers, where CTGF may induce and support the formation of the extensive fibrous connective tissue (desmoplasia) around the cancer. The cells in the dense tissue capsule, such as myofibroblasts and stellate cells, may further support tumor growth through the secretion of growth factors including CTGF and also through the shielding the tumor from chemotherapy agents. Desmoplastic cancers include pancreatic, breast, glioblastoma, and sarcomas (Wenger, C, et al. Oncogene 1999; 18:1073-1080; Ryu, B., et al. Cancer Res. 2001; 61:1833-1838; Iacobuzio-Donahue C. A., et al. Am J Pathol. 2002 January; 16(1):91-9).
Results from nonclinical models of pancreatic cancer demonstrate that blocking the expression or activity of CTGF reduces tumor growth and metastasis (Aikawa T, et al. Mol. Cancer Ther. 2006 May; 5(5):1108-16; Dornhöfer N, et al. Cancer Res. 2006; 66:5817-27; Bennewith K, et al. Cancer Res. 2009; 69:775-784; U.S. Application Publication No. US2005/0271670). Given the intractable nature of pancreatic and other CTGF-associated cancers, therapies that directly intervene with the expression or activity of CTGF are needed. The treatment methodologies and regimens disclosed herein address this need.